tbuckley/cabot-search huggingface dataset:
Abstract 3450: Impact of model inaccuracy on dose estimation in TTFields therapy
Authors: Tal Marciano, Oshrit Zeevi, Zeev Bomzon
Journal: Cancer Research (2022)

Abstract Introduction: Tumor Treating Fields (TTFields) is a modality for treating Glioblastoma (GBM). A recent study combining clinical data and simulations demonstrated that the simulation-based dose estimation at the tumor level is directly correlated with patient survival (Ballo M, et al. Int J Radiat Oncol Biol Phys. 2019;104(5):1106-1113). This study highlights the importance of computer-modelling based TTFields treatment planning in the clinic. Performing such planning in a meaningful manner requires an understanding about how inaccuracies in the patient model influence calculated TTFields distributions. In this study we show the effect of local perturbations in the model, errors in tumor segmentation, and inaccuracy in the patient head model on TTFields dose estimation. Methods: Computational studies were performed with Sim4Life software. 1) Local model uncertainty outside of tumor region: To create defects in the models, conductive spheres with varying conductivities and radii were placed into the model’s brains at different distances from the tumor. Virtual transducer arrays were placed on the models, and delivery of TTFields numerically simulated. The error in the electric field induced by the defects as a function of defect conductivity, radius, and distance to tumor was investigated. 2) Tumor segmentation uncertainty: For illustrating segmentation errors in tumors and necrotic cores, layered spheres with various conductivities and radii were placed in different head locations. Tumor conductivity uncertainty was defined as (σ-σref)/σref where σref = 0.24 S/m is the standard tumor conductivity and σ is the varied conductivity over the tumor. The normalized tumor radius was calculated when each of the varied radii was normalized to the results obtained by all the other combinations. Results: The results show that that when a defect of radius R is placed at a distance, d, from the tumor that is larger than seven times R, the error is below 1% regardless of the defect conductivity. Conclusions: Our models and results show the impact of uncertainty in segmentation of the tumor or other tissue distant from it on the TTFields dose estimation. These results could serve as a guideline for model creation and tissue segmentation that would lead to optimal dose estimation in TTFields treatment planning. Citation Format: Tal Marciano, Oshrit Zeevi, Zeev Bomzon. Impact of model inaccuracy on dose estimation in TTFields therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3450.
Abstract 1436: ABCF1 and ABCF2 genetic variants in association with hepatocellular carcinoma (HCC) risk
Authors: Philip Chun Yeung, Kelvin Kwok Chai Ng, Tan To Cheung, Charing Ching-Ning Chong, Paul Bo San Lai, Siu Tim Cheung
Journal: Cancer Research (2022)

Abstract Background/Aims: ATP-binding cassette (ABC) transporters have been shown to regulate tumor initiating cells in various cancer types and specific genotype associated with cancer risk. ABCF1 was on priority among the ABC transporters because the gene located at 6p21, the chromosome region associated with a number of HCC risk genetic loci including the HLA genes. Its family member ABCF2 was also examined as their expression levels were highly correlated and associated with HCC recurrence. Subjects and Methods: A total of 300 HCC and 300 healthy blood samples (99.3% and 94.7% Chinese respectively) were prospectively collected with informed consent. All patients had been diagnosed with primary HCC and underwent partial hepatectomy. Clinical information including sex, age, tumor stage and survival outcomes were collected prospectively. Genomic DNA were extracted from blood samples and SNPs were examined by TaqMan genotyping assay, Sequenom MassARRAY platform and direct sequencing. Results: Sixteen SNPs and three INDELs were examined in ABCF1 and ABCF2 in the germline DNA of 300 HCCs and 300 healthy individuals. Among the 19 loci investigated, ABCF1 rs1264440 (916-99A&amp;gt;G) and rs4148252 (*1delA), ABCF2 rs3823589 (-43+219C&amp;gt;A) and rs75100208 (368-94C&amp;gt;A) were significantly associated with HCC risk (OR: 1.424, 95%CI: 1.03-1.97, P=0.032; OR: 1.446, 95%CI: 1.04-2.00, P=0.026; OR: 1.635, 95%CI: 1.09-2.46, P=0.018; OR: 1.479, 95%CI: 1.09-2.18, P=0.049, respectively). Patients with any two of the four variant genotype, compared with those with all wild type, revealed elevated HCC risks (OR: 1.657, 95%CI: 1.16-2.37, P=0.006). Importantly, patients with all four variant genotypes demonstrated augmented HCC risk (OR: 2.295, 95%CI: 1.27-4.15, P=0.006). Conclusions: ABCF1 genetic variants rs1264440, rs4148252 and ABCF2 genetic variants rs3823589, rs75100208 were associated with significantly increased HCC risk. Augmented cancer risk was observed among patients possessed all four variant genotypes in ABCF1 and ABCF2. Further mechanistic studies are warranted to comprehend the underlying mechanisms. Citation Format: Philip Chun Yeung, Kelvin Kwok Chai Ng, Tan To Cheung, Charing Ching-Ning Chong, Paul Bo San Lai, Siu Tim Cheung. ABCF1 and ABCF2 genetic variants in association with hepatocellular carcinoma (HCC) risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1436.
Abstract 3642: The aged lung promotes reactivation from metastatic melanoma dormancy
Authors: Mitchell Fane, Ashani Weeraratna
Journal: Cancer Research (2022)

Abstract Our previous data have indicated that while tumors grow more slowly in aged mouse skin, they form more lung metastases. We queried whether the lung microenvironment undergoes age-related changes that provide a permissive niche for metastatic outgrowth. Our data showed that secreted factors by lung fibroblasts changed during aging that promoted proliferation of melanoma cells via expression of the tyrosine kinase receptor MER. Further investigation of this MER-high phenotype revealed that these melanoma cells induce dramatic changes to the lung microenvironment via secretion of its primary ligand PROS1, which creates a more permissive niche for metastasis. It first acts in a paracrine manner to induce proliferation of previously dormant melanoma cells in the lung. MER induced secretion of PROS1 by melanoma cells also regulates the production of extracellular matrix (ECM) from lung fibroblasts. Specifically, healthy human lung fibroblasts produce thick, unified cellular derived matrices (CDMs) in vitro that are growth-restrictive to melanoma cells. Treatment of lung fibroblasts with conditioned media from MER-High melanoma cells or with recombinant-PROS1 alters CDM density and orientation, which resulted in a CDM that dramatically increased melanoma proliferation. Finally, we found that MER induced metastatic outgrowth of melanoma cells within the lungs of mice decreased CD4 and CD8 T-cells whilst increasing infiltration of and immunosuppressive T-regulatory cells (Tregs) and Myeloid Derived Suppressor Cells (MDSCs). Overall, we find that age-induced activation of melanoma cells towards a MER-high state within the lung can induce a cancer phenotype which dramatically alters fibroblast ECM production and immune cell infiltration to promote aggressive and efficient metastatic outgrowth and a growth permissive microenvironment for dormant melanoma cells. Citation Format: Mitchell Fane, Ashani Weeraratna. The aged lung promotes reactivation from metastatic melanoma dormancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3642.
Abstract 5136: Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib
Authors: Megumi Kuronishi, Yoichi Ozawa, Takayuki Kimura, Yu Kato
Journal: Cancer Research (2022)

Abstract Lenvatinib is a multiple receptor tyrosine kinase inhibitor and an angiogenesis inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. In our previous study, we reported that human xenograft tumors sensitive to lenvatinib showed higher microvessel density (“MVD (IHC)”) than relatively resistant tumors in immunohistochemistry (IHC). Although MVD (IHC) is a potential indicator to predict antitumor activity of lenvatinib, available IHC data are limited. Here, we investigated a novel gene expression signature (MVD gene score) calculated from RNA-sequencing (RNA-seq) data that reflects MVD (IHC) and antitumor effect of lenvatinib. Tumor tissues were collected from 12 mouse syngeneic tumor models followed by RNA-seq. We also stained CD31 in the same tumors and calculated MVD (IHC) score by dividing the number of CD31 positive blood vessels by tumor area. Genes that met the following criteria were selected for MVD gene score calculation: (1) genes that are specifically expressed on endothelial cell cluster in in-house single cell RNA-seq data using Hepa 1-6 mouse hepatocellular carcinoma tumor tissues; (2) well-known angiogenesis markers from literature or genes whose expression show significant correlation with MVD (IHC) in mouse syngeneic tumor models. MVD gene score was calculated as the average of logarithm transformed gene expression values. In order to examine applicability of MVD gene score, we compared MVD (IHC) and MVD gene score to lenvatinib antitumor activities on mouse syngeneic tumors. We measured MVD (IHC) and computed MVD gene score from RNA-seq data using matched tumor tissues of 12 mouse syngeneic models. MVD gene score was correlated with MVD (IHC). As reported, lenvatinib sensitive tumor models showed higher MVD (IHC) score. They also showed higher MVD gene score calculated from RNA-seq data. Our newly developed MVD gene score has a potential to predict the antitumor activity of angiogenic inhibitors such as lenvatinib using RNA-seq data in tumor samples. Further validation study is ongoing using various human tumor samples. Citation Format: Megumi Kuronishi, Yoichi Ozawa, Takayuki Kimura, Yu Kato. Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5136.
Abstract 2816: A novel <i>in vivo</i> model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy
Authors: Jiwon Yang, Won Lee, Jing Jiao, Danying Cai, Heather Gustafson, Rebecca Gardner, Mingshan Cheng, James G. Keck
Journal: Cancer Research (2022)

Abstract Over the past few years, chimeric antigen receptor T (CAR T)-cell therapy has emerged as a novel treatment option for certain hematologic malignancies. Several CAR T-cell therapies produced highly efficacious responses from patients with hematologic malignancies. However, wider adoption of CAR T-cell therapy is challenged due to the potential development of life-threatening toxicities including cytokine release syndrome (CRS). CRS symptoms can range from mild fever to life-threatening events, including death. Preclinical animal models to assess the efficacy and toxicity of CAR T-cell therapies have been lacking. Here, we developed a novel mouse model to assess the efficacy and toxicity of CAR T-cell therapy simultaneously. Two different PBMC humanized NSG™ variants were used. NSG-MHC Class I/II double knock-out strain is known to have a delayed onset of GvHD, and NSG-SGM3xIL15 strain shows a higher engraftment level of human NK and myeloid cells, in addition to human T cells. Mice were humanized using PBMCs and treated with autologous or allogeneic CAR T cells, and efficacy and toxicity were assessed. Compared to the control treatment, CD19 CAR T-cells caused a decrease in the human CD19+ cell population in the blood and spleen, and induced cytokine release. Both T-cell and myeloid cytokine releases, including IFNgamma, IL-10, RANTES, and MIP-1alpha, were induced in our animal models. The in vivo platform can also be used to determine individual PBMC/CAR T donor differences and show the extent of efficacy and toxicity of each PBMC donor treated with autologous and allogeneic CAR T-cell therapy. We further confirmed anticancer efficacy using luciferase-tagged human B-cell lymphoma Raji tumor cells, which express a high level of CD19. In summary, we have developed a novel in vivo model to test the efficacy and toxicity of both autologous and allogeneic CAR T-cell therapy simultaneously. Citation Format: Jiwon Yang, Won Lee, Jing Jiao, Danying Cai, Heather Gustafson, Rebecca Gardner, Mingshan Cheng, James G. Keck. A novel in vivo model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2816.
Abstract 1494: 5-methyltetrahydrofolate (5-MTHF) as a superior ligand for delivery of small RNAs for cancer therapy
Authors: Sudarsan R. Kasireddy, Ahmed M. Abdelaal, Philip S. Low, Andrea L. Kasinski
Journal: Cancer Research (2022)

Abstract MicroRNAs (miRNAs) are small noncoding RNAs that regulate a wide array of genes. Because miRNA downregulate translation proteins associated with cancer progression, miRNA-based therapeutics have great potential as anticancer drugs. Nonetheless, the therapeutic potential of miRNA replacement is limited due to lack of safe and efficient delivery vehicles, and inability to target miRNAs to the intended cells/tissues. Thus, identifying molecules that are able to deliver therapeutic miRNA is of critical need. This could be achieved by targeting receptors that are overexpressed on target tumor cells. For example, the folate receptor (FR) is overexpressed on various tumor types including breast, lung, ovarian and brain tumors. Our laboratory has previously developed a unique strategy that directly links a miRNA mimic to the high affinity FR ligand, folate (FolamiRs). In the present work, to further improve the potency of FolamiRs, we introduce the reduced folate metabolite, 5-methyltetrahydrofolate (5-MTHF) that maintains nanomolar affinity for the FR at pH 7, but disengages from the FR at a significantly higher pH than that of folate, which is important when including an endosomal escape agent that typically disrupts endosomal acidification. We synthesize and conjugate 5-MTHF ligand to the potent tumor suppressor miRNA-34a (5-MTHF-miR-34a). We show that 5-MTHF-miR-34a uptake is specific to the cells overexpressing FR and represses target gene expression. Our data supports the use of 5-MTHF in combination with the endosomal escape agent, nigericin, to achieve robust cytosolic localization of therapeutically relevant miRNAs such as miR-34a. This work provides the foundation for future studies using 5-MTHF- conjugated therapeutic agents for targeting additional FR expressing cells, including myeloid derived suppressor cells (MDSCs) and macrophages. Collectively these studies will pave the way for developing 5-MTHF-based small RNA conjugates for treating FR-expressing cancers. The details of these intriguing results will be discussed in the poster. Citation Format: Sudarsan R. Kasireddy, Ahmed M. Abdelaal, Philip S. Low, Andrea L. Kasinski. 5-methyltetrahydrofolate (5-MTHF) as a superior ligand for delivery of small RNAs for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1494.
Abstract 3881: Immune profiling of advanced prostate cancer harboring homologous recombination deficiency
Authors: Maryam Soleimani, Sonia Kung, Neetu Saxena, Ladan Fazli, Lucia Nappi
Journal: Cancer Research (2022)

Abstract Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 6-8% of patients with localized PCa and up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumor microenvironment (TME) associated with HRD is poorly understood. We used PCa tumors of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumor immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n=13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumor cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n=104), neoadjuvant hormone therapy treated (NHT) (n=16), neuroendocrine (NEPC) (n=41) and CRPC (n=22) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations,BRCA1/2 were the most frequently identified (BRCA1/2n=6, FANCCn=1, FANCD2=2, PALB2=1, CDK12n=1, ATRn=2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens and were more abundant compared to NEPC (p≤ 0.05) and untreated tumors (p≤0.01). The HRD cohort had higher levels of A2aR, in TC and SL (p≤0 .0001 for both) and higher levels of PD-L2 in TC (p≤0.0001) compared to all other cohorts and in the SL (p≤0.05) compared to untreated, CRPC and NEPC cohorts. Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort, and in HRD cohort SL compared to all cohorts (p≤0.0001 for both). There was no difference in TIM-3 or GAL9 expression. Conclusions: Evaluation of stromal and tumor cell immune profiling indicates that compared to other subtypes, PCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable immunotherapeutic pathways which may render clinical benefit in this patient population. Citation Format: Maryam Soleimani, Sonia Kung, Neetu Saxena, Ladan Fazli, Lucia Nappi. Immune profiling of advanced prostate cancer harboring homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3881.
Abstract 2640: Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism
Authors: Trace M. Jones, Claudia M. Espitia, Aikseng Ooi, Julie E. Bauman, Jennifer S. Carew, Steffan T. Nawrocki
Journal: Cancer Research (2022)

Abstract Patients with late-stage and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival and overcome drug resistance is an urgent priority. We, and others, have reported that HNSCC tumors significantly overexpress NEDD8 and exhibit high sensitivity to the first-in-class NEDD8 activating enzyme (NAE) inhibitor pevonedistat. Here, we report that disruption of NEDD8-mediated protein turnover with pevonedistat dramatically augments cisplatin-induced DNA damage and apoptosis in HNSCC models. Further analysis revealed that the specific pevonedistat target, CUL4A, played an essential role in driving the synergy of the pevonedistat and cisplatin combination. Targeted inhibition of CUL4A resulted in significant downregulation in Damage Specific DNA binding protein 2 (DDB2), a DNA-damage recognition protein that promotes nucleotide excision repair and resistance to cisplatin. Silencing of CUL4A enhanced cisplatin-induced DNA damage and apoptosis in a manner similar to that of pevonedistat demonstrating that targeted inhibition of CUL4A may be a novel approach to augment cisplatin therapy. Administration of pevonedistat to mice bearing HNSCC tumors significantly decreased DDB2 expression in tumor cells, increased DNA damage and potently enhanced the activity of cisplatin to yield tumor regression and long-term survival of all animals. Our findings provide strong rationale for clinical investigation of CUL4A inhibition with pevonedistat as a novel strategy to augment the efficacy of cisplatin therapy for patients with HNSCC and identify loss of DDB2 as a key pharmacodynamic mediator controlling sensitivity to this regimen. Citation Format: Trace M. Jones, Claudia M. Espitia, Aikseng Ooi, Julie E. Bauman, Jennifer S. Carew, Steffan T. Nawrocki. Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2640.
Abstract 3896: Pimavanserin suppresses the growth of medulloblastoma by inhibiting Lyn/STAT3/MBSC signaling axis
Authors: Sharavan Ramachandran, Shreyas Gaikwad, Sanjay K. Srivastava
Journal: Cancer Research (2022)

Abstract Medulloblastoma (MB) is one of the most frequently occurring malignant brain tumors in children, which accounts for 20% of all pediatric brain tumors and 40% of posterior fossa tumors. Despite advancements in the understanding of MB pathogenesis and identification of novel therapeutic targets, MB has emerged to be one of the most lethal pediatric diseases with peak incidences occurring in children aged between 5 and 7 years old. Numerous factors have been identified to hamper the management of several brain tumors including MB. However, the presence of medulloblastoma stem cells (MBSCs) and impermeability of drugs to cross the blood brain barrier (BBB) are identified as the major obstacles in MB management. MB is highly enriched with MBSCs, a subpopulation of MB cells that imparts therapy resistant, invasive and recurrent characteristics to MB. In our study, we evaluated the effects of Pimavanserin (PVT) in MB. Our results demonstrated that PVT treatment suppressed the proliferation of various MB cells by inducing apoptosis as shown by AnnexinV APC-PI assay. At molecular level, PVT inhibits Lyn/STAT3/MBSCs signaling axis. Additionally, chronic administration of PVT significantly suppressed the growth of subcutaneous and intracranial tumor xenografts without causing major side effects. Taken together, our study provides convincing evidence that PVT could serve as a novel treatment option for MB patients in the future. Ours is the first study to report to report the anti-cancer effects of PVT. Citation Format: Sharavan Ramachandran, Shreyas Gaikwad, Sanjay K. Srivastava. Pimavanserin suppresses the growth of medulloblastoma by inhibiting Lyn/STAT3/MBSC signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3896.